Cancer: A Problem of Developmental Biology; Scientific Evidence for Reprogramming and Differentiation Therapy.

Current medical literature acknowledges that embryonic micro-environment is able to suppress tumor development. Administering carcinogenic substances during organogenesis in fact leads to embryonic malformations, but not to offspring tumor growth. Once organogenesis has ended, administration of carcinogenic substances causes a rise in offspring tumor development. These data indicate that cancer can be considered a deviation in normal development, which can be regulated by factors of the embryonic microenvironment. Furthermore, it has been demonstrated that teratoma differentiates into normal tissues once it is implanted in the embryo. Recently, it has been shown that implanting a melanoma in Zebrafish embryo did not result in a tumor development; however, it did in the adult specimen. This demonstrates that cancer cells can differentiate into normal tissues when implanted in the embryo. In addition, it was demonstrated that other tumors can revert into a normal phenotype and/or differentiate into normal tissue when implanted in the embryo. These studies led some authors to define cancer as a problem of developmental biology and to predict the present concept of "cancer stem cells theory". In this review, we record the most important researches about the reprogramming and differentiation treatments of cancer cells to better clarify how the substances taken from developing embryo or other biological substances can induce differentiation of malignant cells. Lastly, a model of cancer has been proposed here, conceived by one of us, which is consistent with the reality, as demonstrated by a great number of researches. This model integrates the theory of the "maturation arrest" of cancer cells as conceived by B. Pierce with the theory which describes cancer as a process of deterministic chaos determined by genetic and/or epigenetic alterations in differentiated cells, which leads a normal cell to become cancerous. All the researches here described demonstrated that cancer can be considered a problem of developmental biology and that one of the most important hallmarks of cancer is the loss of differentiation as already described by us in other articles.

Getting an Insight into the Complexity of Major Chronic Inflammatory and Degenerative Diseases: A Potential New Systemic Approach to Their Treatment.

As the modern society is troubled by multi-factorial diseases, research has been conducted on complex realities including chronic inflammation, cancer, obesity, HIV infection, metabolic syndrome and its detrimental cardiovascular complications as well as depression and other brain disorders. Deterioration of crucial homeostatic mechanisms in such diseases invariably results in activation of inflammatory mediators, chronic inflammation, loss in immunological function, increased susceptibility to diseases, alteration of metabolism, decrease of energy production and neuro-cognitive decline. Regulation of genes expression by epigenetic code is the dominant mechanism for the transduction of environmental inputs, such as stress and inflammation to lasting physiological changes. Acute and chronic stress determines DNA methylation and histone modifications in brain regions which may contribute to neuro-degenerative disorders. Nuclear glucocorticoids receptor interacts with the epigenoma resulting in a cortisol resistance status associated with a deterioration of the metabolic and immune functions. Gonadal steroids receptors have a similar capacity to produce epigenomic reorganization of chromatine structure. Epigenomic-induced reduction in immune cells telomeres length has been observed in many degenerative diseases, including all types of cancer. The final result of these epigenetic alterations is a serious damage to the neuro-endocrine-immune-metabolic adaptive systems. In this study, we propose a treatment with stem cells differentiation stage factors taken from zebrafish embryos which are able to regulate the genes expression of normal and pathological stem cells in a different specific way.

Stem Cell Differentiation Stage Factors from Zebrafish Embryo: A Novel Strategy to Modulate the Fate of Normal and Pathological Human (Stem) Cells.

In spite of the growing body of evidence on the biology of the Zebrafish embryo and stem cells, including the use of Stem Cell Differentiation Stage Factors (SCDSFs) taken from Zebrafish embryo to impact cancer cell dynamics, comparatively little is known about the possibility to use these factors to modulate the homeostasis of normal human stem cells or to modulate the behavior of cells involved in different pathological conditions. In the present review we recall in a synthetic way the most important researches about the use of SCDSFs in reprogramming cancer cells and in modulating the high speed of multiplication of keratinocytes which is characteristic of some pathological diseases like psoriasis. Moreover we add here the results about the capability of SCDSFs in modulating the homeostasis of human adiposederived stem cells (hASCs) isolated from a fat tissue obtained with a novel-non enzymatic method and device. In addition we report the data not yet published about a first protein analysis of the SCDSFs and about their role in a pathological condition like neurodegeneration.

The PI3K-AKt-mTOR Pathway and New Tools to Prevent Acquired Hormone Resistance in Breast Cancer.

Acquired hormone resistance is an old hurdle and still represents to be a constant challenge in oncology for the medical community. Most recently, mainly following the results of BOLERO-2 study, the activation of the PI3K-AKT-mTOR pathway is considered clinically relevant for tumor escape from hormone dependence in breast cancer. In the BOLERO-2 trial, a combination of everolimus, mTOR inhibitor, and exemestane significantly prolonged the median progression free survival (PFS) compared to exemestane alone in advanced breast cancer patients with acquired endocrine resistance. Therefore, the inhibitors of the PI3K-AKT-mTOR pathway are a new class of drugs in great expansion joined with great expectation. This review article focuses on this special issue and briefly reports on the results of clinical trials using PI3K-AKT-mTOR inhibitors. However, the emergence of resistance to this new class of drugs, evidenced by the basic research and the relatively less benefit shown in the clinical trials, has been emerging as a new undesirable complication. Therefore, the principal elucidated mechanisms of the resistance to the inhibitors of the PI3K-AKT-mTOR pathway and the related potential therapeutic strategies are described. A more general immunological approach to delay acquired hormone resistance has also been considered and commented upon.